The factors that cause normally harmless episodes of inflammation to culminate in disease are largely[unreadable] unknown but likely include genetic and environmental influences. Exposure to environmental chemicals such[unreadable] as aryl hydrocarbon receptor (AhR) ligands could contribute to individual susceptibility to disease by[unreadable] enhancing inflammatory responses or by providing a stimulus that precipitates injury in the presence of[unreadable] inflammation. Indeed, in preliminary studies, mice developed liver injury when coexposed to TCDD (2,3,7,8-[unreadable] tetrachlorodibenzo-p-dioxin) and the inflammatory stimulus, lipopolysaccharide (LPS), each at doses that[unreadable] alone did not cause liver damage. The goal of the proposed research is to test the hypothesis that Ah[unreadable] receptor ligands enhance inflammatory responses that can lead to tissue injury. Consistent with the overall[unreadable] goal of the Program Project, the tissue of interest for this project is liver. This hypothesis will be tested by first[unreadable] evaluating the development of LPS-induced inflammation in mice exposed to AhR ligands and by delineating[unreadable] the dose-response relationship for AhR ligand-induced liver injury in the absence and presence of[unreadable] inflammation. The AhR ligands to be used are TCDD and 3,3',4,4',5-pentachlorobiphenyl (PCB 126). Mice[unreadable] will be treated with AhR ligands alone or in combination at doses that are not hepatotoxic. They will then be[unreadable] treated with a small dose of LPS that induces inflammation but alone does not cause liver injury. Markers of[unreadable] inflammation and liver injury will be assessed and time-courses and dose-response relationships[unreadable] established. Global changes in hepatic gene expression and DMA methylation in these dose-response and[unreadable] time-course studies will be determined by microarray analysis and will be compared to biochemical and[unreadable] histological changes in liver as well as to markers of inflammation. Both neutrophils and the hemostatic[unreadable] system, including plasminogen activator inhibitor-1 (PAI-1), are critical to liver injury in many models of[unreadable] chemical-inflammation interactions. To begin to understand inflammatory mediators that contribute to liver[unreadable] injury during AhR-inflammation interactions, the roles of neutrophils and components of the hemostatic[unreadable] system will be investigated in mice exposed to TCDD in the presence of inflammation. Tumor necrosis[unreadable] factor alpha (TNF) is a proinflammatory cytokine that is reported to mediate LPS-induced increases in[unreadable] expression of PAI-1 in vivo. In preliminary studies treatment of mice with either TCDD or LPS increased[unreadable] serum concentration of PAI-1 expression, but the combination had a synergistic effect. Accordingly, a[unreadable] computational description of the biochemical pathways by which AhR ligands induce changes in expression[unreadable] of PAI-1 in the absence and presence of inflammation will be developed. The results of these studies[unreadable] collectively will provide information about consequences of the interactions between inflammatory responses[unreadable] and AhR ligands and about molecular mechanisms involved in this interaction.